Project 4 of this Superfund Basic Research Program (SBRP) explores the genetic basis of sensitivity to environmentally induced birth defects. It has long been appreciated that gene-environment interactions serve to regulate many complex disease processes, including the determination of the phenotypes of infants exposed in utero to environmental toxins. There is now a growing and compelling experimental body of evidence that in utero exposure to inorganic arsenic disrupts normal embryonic development resulting in significant congenital anomalies, including neural tube defects (NTDs) and craniofacial malformations. It has also been established that periconceptional folate supplementation reduces the risk for NTDs and cleft lip and palate in humans, utilizing a yet unknown mechanism. This alone has a multi-billion dollar impact on US public health care dollars. The proposed research program will attempt to address these two issues and enhance our understanding of the mechanisms underlying the genetic and environmental interactions, following in utero exposure to arsenate as a model environmental toxicant and one that is highly relevant to the SBRP. We will utilize state-of-the-art genomic approaches with three novel, genetically modified mouse strains that lack the ability to bind and transport folate molecules. It is hypothesized that those mice that are folate deplete will be at increased risk for malformations due to the arsenic exposure given that the primary means of detoxification is via folate-dependant methylation reactions. In support of the genetic microarray analyses of neuroepithelial and neural crest cells obtained from the developing neural tube and craniofacial tissues, we will apply an intensive bioinformatics analysis of the expression profiles in these model systems, to enable us to track the molecular fingerprint of neural tube and craniofacial development, and learn how folate regulates these events. We will also examine epigenetic factors that are compromised by teratogen exposure in these same model systems. The scope of the studies is such that we will obtain a comprehensive understanding of genetic and epigenetic factors that regulate sensitivity to environmentally-induced birth defects.